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PubMed2026

Ascites Bactericidal Capacity in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: Patients with decompensated cirrhosis are at high risk of developing bacterial infections. The most common infection is spontaneous bacterial peritonitis in ascites fluid, caused by gut bacterial translocation and facilitated by cirrhosis associated immune dysfunction. Common causative agents of spontaneous bacterial peritonitis are thought to represent pathobionts that increase in abundance in the gut with cirrhosis severity, rather than opportunistic commensals. Despite this there have been few studies describing the characteristics of spontaneous bacterial peritonitis pathogens and immune responses to them. METHODS: We investigated the bactericidal capacity of cell-free ascites fluid and ascites macrophages. RESULTS: Nonpathogenic Escherichia coli K12 was rapidly killed in cell-free ascites fluid, whereas extraintestinal pathogenic E coli and Klebsiella pneumoniae strains, representative of the most common causes of spontaneous bacterial peritonitis, were resistant. A transposon-based genome-wide screen identified a requirement for genes involved in O-antigen biosynthesis for survival of both organisms in cell-free ascites fluid, including the transcription factor RfaH, which controls expression of surface polysaccharides. Although extraintestinal pathogenic E coli were resistant to fluid-mediated killing, ascites macrophages, especially VSIG4Hi cells, phagocytosed and killed extraintestinal pathogenic E coli and nonpathogenic E coli K-12 with similar efficacy. Mice with toxin-induced cirrhosis had higher bacterial burdens in the liver compared with control mice when infected with extraintestinal pathogenic E coli, but rapidly cleared an rfaH mutant attenuated for capsule and O-antigen biosynthesis. CONCLUSIONS: These data highlight the importance of understanding bacterial virulence profiles in addition to taxonomy in cirrhosis dysbiosis and identify critical roles for capsule and O-antigen in host evasion by spontaneous bacterial peritonitis-associated pathogens. Targeting bacterial virulence factors and/or host macrophage functions may reduce the risk of spontaneous bacterial peritonitis in cirrhosis.

Animals↗
PubMed2001

Impairment of antigen-specific cellular immune responses under simulated microgravity conditions.

Microgravity has been implicated to play a role in the observed immune dysfunction of astronauts and cosmonauts after either short-term or long-term space travel. These reports, together with studies describing increased levels of microorganisms in the space cabin environment suggest potential risk for in-flight incidences of infectious diseases. In order to understand the mechanism underlying these immune defects, it is important to have a ground-based model that would reliably mimic the effects of microgravity on antigen-specific immune function. We tested the utility of the rotating wall vessel (RWV) technology developed at NASA as a model system because in the RWV the culture medium and the cells rotate synchronously with the vessel, thereby creating simulated microgravity conditions. We compared the RWV to the conventional tissue culture flask (T-flask), for culturing immune precursor cells with cytotoxic T lymphocyte (CTL) activity against synthetic viral peptides. We observed a significant loss of antigen-specific CTL activity in RWV cultures, but not in those from the T-flask, irrespective of the peptide immunogen used for inducing the primary immune response in different mouse strains. Loss of CTL activity in RWV cultures coincided with a significant reduction in CD8+ cells as well as CD4+ cells and DEC205+ dendritic cells, suggesting adverse effects of RWV culturing on both the effector and accessory cells for the loss of antigen-specific CTL function. These results provide a strong parallel to the reported defects in cell-mediated immunity during space travel and strongly support the utility of the RWV technology as an effective ground-based model for identifying key steps in immune cell dysfunction related to microgravity.

Amino Acid Sequence↗
PubMed2006

Experimental frontiers for clinical applications: novel approaches to understanding mechanisms of lymph node metastases in melanoma.

Sentinel lymph nodes are the first nodes to receive lymph from primary tumors and are the preferential site of initial metastases. Sentinel nodes show morphology changes that suggests immune modulation with reduced antigen-presenting dendritic cells, activated T lymphocytes, high endothelial venules and transvenular migration of T lymphocytes. Tumor cells generate down-regulatory molecules. We postulate that tumor-induced immune dysfunction facilitates establishment of nodal metastases. Nodal immune modulation can be reversed by granulocyte macrophage colony-stimulating factor (GMCSF), a finding with implications for future therapy to prevent or reverse these nodal metastases.

Animals↗
PubMed2006

New cytokine targets in inflammatory rheumatic diseases.

With the advent of biological therapies, considerable advances have been achieved in the treatment of inflammatory arthritis. These have arisen primarily from studies elucidating mechanisms of pathophysiology and are best exemplified in the wide use of tumour necrosis factor (TNF) blockade in several rheumatic diseases. The identification of additional pro-inflammatory factors in rheumatic diseases and an understanding of their effector function, now offers major possibilities for the generation of novel therapeutics. To address unmet clinical need, such interventions will ideally fulfil several of the following criteria: (1) control of inflammation, (2) modulation of underlying immune dysfunction - promoting the re-establishment of immune tolerance, (3) protection of targeted tissues such as bone and cartilage - this should encompass promoting healing of previously damaged tissues, (4) preservation of host immune capability - to avoid profound immune suppression and (5) amelioration of co-morbidity associated with underlying inflammatory arthritis. This short review will consider those novel cytokine activities that represent optimal utility as therapeutic targets. Since we wish to reflect the current predominant research effort, we will focus primarily on rheumatoid arthritis (RA) based studies.

Animals↗
PubMed2000

Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice.

Numerous studies have demonstrated the efficacy of cytokine gene-engineered tumor cells to induce tumor rejection and specific memory acquisition into syngeneic immunocompetent mice by activation of host-dependent antitumor responses. A progressive immune dysfunction, mainly involving thymus-dependent specific immunity, occurs during aging. In this study we evaluated whether the injection of IL-2 gene-transfected tumor cells in old mice causes an immune activation which results in tumor rejection and induction of specific immune memory as occurs in young animals. Young and old mice were inoculated with syngeneic parental mammary adenocarcinoma cells (TS/A p.c.) or with TS/A cells engineered to release IL-2 (TS/A-IL2). Three clones of TS/A-IL-2 cells were used producing low (30 U, B1.30), intermediate (3600 U, B6.3600), or high (6000 U, B4.6000) IL-2. While the B1.30 clone grew in 100% of mice, the B6.3600 and B4.6000 clones were promptly rejected in both young and old animals. In young mice, rejection was associated with a large neutrophil and macrophage infiltration, with a minor number of CD4+ and CD8+ lymphocytes. In old mice, neutrophils and macrophages were the main cells involved in tumor rejection whereas both CD4+ and CD8+ lymphocytes were scarcely present in tumoral infiltrate. A lower number of apoptotic tumor cells was found in TS/A-IL2-challenged old mice in comparison with young animals. To test whether the injection of TS/A-IL2 cells induced a specific immune memory, mice with no tumors after the challenge with B6.3600 and B4.6000 clones received a lethal challenge of TS/A p.c. 90% and 30% of young mice previously injected with B4.6000 or B6.3600 clones, respectively, rejected TS/A p.c. In old mice, B4.6000 cells did not confer protection, whereas only 10% of mice which received B6.3600 cells were able to reject TS/A p.c. Neither the graft of a young thymus or the adoptive transfer of young T lymphocytes to old mice induced specific immune memory for TS/A p.c. in old animals. These data suggest the necessity to refine antitumor vaccination procedures in aging.

Adenocarcinoma↗
PubMed2002

Stem-cell transplantation for primary immunodeficiencies.

Until further improvement in gene therapy is achieved, stem-cell transplantation is still the main option for cure of patients with primary immunodeficiency diseases. Performing the transplant in early infancy before severe infections and organ damage develop has the highest chance for success. The remarkable progress that has been achieved in understanding these disorders has made it possible to identify most of the genetic abnormalities. This enables an early transplant immediately after birth or even in utero. However, the optimal approach for stem-cell transplantation in children with immunodeficiency has yet to be determined. The non-myeloablative protocols increasingly used in recent years have the potential for immune reconstitution without considerable toxicity, but the experience is still limited. A better understanding of the specific immune dysfunction and the exact degree of residual immunity may enable the tailoring of the most appropriate conditioning regimen for each patient so that engraftment will be ensured with little morbidity.

Hematopoietic Stem Cell Transplantation↗
PubMed1991

[Auto-cholinergic synapse dysfunction in patients with generalized epileptic seizures. A preliminary report].

The mechanism of epileptic seizures so far remains unclear. Immunological disturbances may be one of the possible mechanisms. The assumption that primary epilepsy is an autoimmune disease lacks an experimental basis. In order to search any relationship between generalized epileptic seizures and autoimmune we examined and measured the serum anti-acetylcholine receptor antibody (A AchR Ab) and anti-synaptic premembrane antibody (A PrM Ab) in 12 patients with typical absences, 20 patients with generalized tonic-clonic seizures (GTC) and 6 patients with Lennox-Gastaut Syndrome. 2 (16.7%) out of 12 patients with absences showed positive both A AchR Ab and A PrM Ab, positive A AchR Ab in 1 patient. Among 20 patients with GTC both A AchR Ab and A PrM Ab were positive in 7 patients (35%), A PrM Ab was positive in 1 patient. Totally in 8 patients A PrM Ab was positive. However, the difference between the two Antibodies was not significant (1.1:1). The two kinds of antibody were positive in 5 (83%) out of 6 patients and A PrM Ab was positive, but A AchR Ab was doubtful in another one patient with Lennox-Gastaut syndrome. Therefore, all the patients with Lennox-Gastaut syndrome showed positive antibody. Our data suggested that different types of generalized epileptic-seizures showed different severity of autoimmune dysfunction. The meaning of this kind of immune dysfunction needs further investigation.

Adolescent↗
PubMed1984

Role of cytomegalovirus in Kaposi's sarcoma.

Previous studies have established an association between cytomegalovirus (CMV) and classic and endemic Kaposi's sarcoma (KS) which can be extended to include the epidemic form of KS. The identification of nucleic acid sequences homologous to CMV but not to Epstein-Barr virus (EBV) and Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) as well as the detection of CMV gene products, particularly early antigens, in tumour biopsies and/or early cultures derived from them is an important criterion in the establishment of the type of association. Detection of CMV early antigens but not late antigens as well as the failure to demonstrate virus particles in primary tumour biopsies rule out a simple passenger role of this virus or a preferential site for virus replication in neoplastic tissue. In the setting of a profound immune dysfunction, as in the case of acquired immune deficiency syndrome (AIDS), renal transplant recipients under immunosuppressive therapy, and other iatrogenically immunosuppressed patients (the three groups in which KS has been most frequently observed), the specific involvement of CMV oncogenes, of which at least two have been so far identified in experimental systems, is strongly indicated. Moreover, in vitro transformation experiments indicate that the virus is clearly involved in the initiation of transformation, while other factors (co-carcinogens, activation of cellular oncogenes?) might be required for the maintenance of the transformed phenotype. Endothelial cells, permissive for CMV infection, might be the prime target for these events, since there is evidence that they are a main constituent of KS tissue. Data obtained during 14 years of research on KS are reviewed and possible etiopathogenetic mechanisms giving rise to this type of tumour are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Frailty and the older man.

Frailty is a wasting syndrome of advanced age that leaves a person vulnerable to falls, functional decline, morbidity, and mortality. The cause of this syndrome is complex but likely has a biologic basis. Studies by the authors' research group have validated a phenotype of frailty [table: see text] and have established a gender difference in prevalence with women twice as likely to develop the syndrome as men. Using a biologic model that includes sarcopenia, neuroendocrine decline, and immune dysfunction as potential causes, several physiologic gender differences may explain these differing levels of frailty. First, higher baseline levels of muscle mass may protect men from reaching a threshold of weakness and muscle mass loss that may put them into a category of frailty. Specific neuroendocrine and hormonal factors that may make men less likely to develop frailty than women include testosterone and GH, which may provide advantages in muscle mass maintenance, and cortisol, which is likely less dysregulated in older men as compared to older women. There is also evidence of immune system dimorphism that is, in part, responsive to sex steroids, perhaps making men more vulnerable to sepsis and infection and women more vulnerable to chronic inflammatory conditions and muscle mass loss. The net effect of the hormonal dysregulation and immune system dysfunction is an accelerated loss of muscle mass. There is also evidence that lower levels of activity and lower caloric intake in women as compared to men may also influence the phenotype of frailty and make women more vulnerable then men to the syndrome.

Black or African American↗
PubMed2001

Immunobiology and immunotherapy of head and neck cancer.

The development of head and neck cancer (HNC) is strongly influenced by the host immune system. Immunoselection of tumors resistant to immune attack and the ability of established tumors to disarm or eliminate immune cells favor tumor progression. Recent evidence for local as well as systemic apoptosis of T lymphocytes, the paucity of dendritic cells (DC) at the tumor site, or the presence of signaling defects in T lymphocytes of patients with HNC emphasizes the fact that their antitumor responses are compromised. The clinical and biologic importance of these immune biomarkers is revealed by the finding that they appear to independently predict 5-year survival in patients with oral carcinoma. Whereas the mechanisms responsible for immune dysfunction in HNC are being investigated, new immunotherapeutic strategies, including antitumor vaccines and DC-based interventions, aim at the restoration of tumor-targeted immune responses. These novel biologic therapies, alone or in combination with conventional therapies, might be expected to protect immune cells from dysfunction or death and to enhance their antitumor activity.

Adjuvants, Immunologic↗
PubMed1984

Behçet's syndrome: immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy.

Immune regulatory dysfunction, circulating immune complexes (CIC), and polymorphonuclear (PMN) cell migration were investigated in patients with Behçet's syndrome. Six patients meeting rigorous clinical criteria were evaluated. Only one patient showed evidence of immune regulatory dysfunction (increased T4/T8 ratio). Although C1q binding and Raji cell assays for CIC yielded positive results in only one of five patients, all five patients had in vivo "histamine trap test" evidence of CIC (all controls had normal results). Sera from all Behçet's syndrome patients increased migration of neutrophils to zymosan-activated serum. Colchicine therapy abolished the enhancing effect of the patient's sera on movement of PMN cells from patients and controls. An immune complex-mediated injury that is followed by an excessive accumulation of PMN cells may lead to the cutaneous lesions and other lesions in Behçet's syndrome. Further evaluation of colchicine therapy is warranted on the basis of these studies.

Adult↗
PubMed1996

T-cell dysfunctions in hu-PBL-SCID mice infected with human immunodeficiency virus (HIV) shortly after reconstitution: in vivo effects of HIV on highly activated human immune cells.

The state of activation of the immune system may be an important factor which renders a host more receptive to human immunodeficiency virus (HIV) and more vulnerable to its effects. To explore this issue with a practical in vivo model, we developed a modified protocol of HIV infection in hu-PBL-SCID mice. First, we assessed the time course of activation of human peripheral blood lymphocytes (hu-PBL) in the peritoneal cavity of SCID mice. At 2 to 24 h after the intraperitoneal injection into SCID mice, there was a clear-cut increase in the percentage of hu-PBL expressing early activation markers (CD69), concomitant with the release of soluble intercellular adhesion molecule-1 (sICAM-1) and the soluble interleukin-2 receptor (sIL-2R) and with the accumulation of mRNAs for a number of human cytokines. At 2 weeks, virtually all of the hu-PBL expressed the memory phenotype (CD45RO) and HLA-DR antigens as well. Cells collected from the SCID mouse peritoneum at 2 and 24 h after transplantation were fully susceptible to in vitro infection with HIV type 1 (HIV-1) in the absence of either IL-2 or mitogens. The injection of HIV into hu-PBL-SCID mice at 2 h after reconstitution resulted in a generalized and productive HIV infection of the xenochimeras. This early HIV-1 infection resulted in a dramatic depletion of human CD4+ cells and in decreased levels of sICAM-1 (in the peritoneal lavage fluid) as well as of sIL-2R and immunoglobulins M and A (in the serum). Enzyme-linked immunosorbent assay and/or reverse transcriptase PCR analysis showed higher levels of IL-4, IL-5, and IL-10 in the HIV-infected animals than in control hu-PBL-SCID mice, while gamma interferon levels in the two groups were comparable. When we compared the current model of HIV-1 infection at 2 weeks after the intraperitoneal injection of the hu-PBL in the SCID mice with the model described here, we found that the majority of immune dysfunctions induced in the 2-h infection of the xenochimeras are not inducible in the 2-week infection. This supports the concept that the state of activation of human cells at the moment of the in vivo infection with HIV-1 is a crucial factor in determining the immune derangement observed in AIDS patients. These results show that some immunological dysfunctions induced by HIV infection in AIDS patients can be mimicked in this xenochimeric model. Thus, the hu-PBL-SCID mouse model may be useful in exploring, in vivo, the relevance of hu-PBL activation and differentiation in HIV-1 infection and for testing therapeutic intervention directed towards either the virus or the immune system.

Animals↗
PubMed2026

GATA2 deficiency: enhancer deregulation, immune surveillance failure, and clonal evolution.

Germline mutations in GATA2 cause a syndromic inborn error of immunity characterized by cytopenia, infections, immune dysregulation, and a marked predisposition to myelodysplastic syndrome and acute myeloid leukemia. Initially defined by the DCML phenotype-dendritic cell, monocyte, B- and NK-cell deficiency-GATA2 deficiency is now recognized as a disorder of global immune-hematopoietic homeostasis. Recent multi-omics and experimental models reveal enhancer-driven inflammatory rewiring, IRF8-dependent lineage imbalance, and premature hematopoietic aging. In parallel, adaptive immune defects, including impaired B- and T-cell development and function, contribute to defective immune surveillance. These alterations not only explain susceptibility to infection but also shape clonal evolution and malignant transformation. Clinically, improved risk stratification and transplant outcomes underscore the importance of early recognition and monitoring of immune dysfunction. GATA2 deficiency thus represents a paradigm linking immune dysregulation, inflammatory stress, and cancer predisposition.

Humans↗
PubMedDate not supplied

Alterations in macrophage-produced cytokines and nitrite associated with poult enteritis and mortality syndrome.

Poult enteritis and mortality syndrome (PEMS) is an acute, transmissible, infectious intestinal disease associated with high mortality and morbidity in turkey poults. Earlier studies demonstrated immune dysfunction, involving both humoral and cell-mediated immunity, associated with PEMS. The current study examined cytokines and metabolites produced by macrophages from poults exposed to PEMS agent(s). Six trials were conducted with six separate hatches of poults. Poults in the PEMS group were exposed to PEMS agent(s) via contact exposure at 7 days of age whereas uninfected poults served as control poults. Abdominal macrophages were harvested from control (uninfected) and PEMS poults at various times postexposure and cultured for 18-24 hr in the presence of Escherichia coli lipopolysaccharide. Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) bioactivities and nitrite levels in macrophage culture supernatants were quantified. Macrophage supernatants from PEMS poults had greater IL-1-mediated stimulation index compared with the macrophage supernatants from uninfected control poults in both trials. However, this increase was significant only in trial 1. IL-6 activity tested in three separate trials was significantly higher in PEMS macrophage supernatants over the controls. On the contrary, TNF-alpha production by macrophages was decreased in PEMS macrophage culture supernatants. Nitrite levels in PEMS macrophage culture supernatants were significantly higher in two out of three trials. These findings suggest that the enhanced production of proinflammatory cytokine/metabolites by activated macrophages in PEMS poults may be responsible, at least in part, for the physiological intestinal inflammation, gut motility, and anorexia that characterize this disease.

Animals↗
PubMedDate not supplied

HIV therapy in the post-eradication era.

Over the past three years, most efforts of virologists and immunologists involved in the field of Human Immunodeficiency Virus (HIV) have been focussed on strategies aimed at eradicating the infection. So far, however, all the approaches have been unsuccessful. Indeed, even if the currently available potent antiretroviral regimens are able to induce a profound and durable suppression of viral replication, they have poor effect on a viral reservoir of latently infected CD4+ T lymphocytes that rapidly reactivate after treatment discontinuation. Different approaches, including combined (immune based and antiretroviral) therapies, are therefore under investigation. The goal is to achieve an equilibrium where virus-induced immune dysfunction is prevented by an effective anti HIV immune response.

Anti-HIV Agents↗
PubMed2004

Immune strategy.

AIDS is a disease of primary immune dysfunction caused by HIV. To date, all of the approved and proven strategies for treating HIV disease focus on crippling the virus' ability to infect and/or destroy these cells. There are no approved treatments directed toward the immune deficits and dysfunctions caused by HIV. The good news is that when HIV replication is slowed through the use of anti-HIV drugs, the immune system begins to repair itself and there is evidence of a degree of immune restoration when HIV is controlled over time.

CD4 Lymphocyte Count↗
PubMed1994

Immunologic and virologic effects of glucocorticoids on human immunodeficiency virus infection in children: a preliminary study.

The immune dysfunction in human immunodeficiency virus (HIV) infection is complex and cannot be explained solely on the basis of numerical depletion of T lymphocytes. Inappropriate, uncontrolled activation of the immune system may be involved. In a test of this hypothesis, five HIV-infected children were prospectively treated with prednisone and selected immunologic and virologic indices were analyzed. Subjects had marked T lymphopenia (CD4+ T lymphocytes < 500 cells/ml) and antigenemia (serum p24 antigen > 30 pg/ml) and were free of opportunistic infections. There was a significant drop in serum p24 antigen concentrations from baseline (60.2 +/- 10.1% SEM; P < 0.005) 4 weeks after initiation of prednisone, which returned to baseline concentrations as the prednisone was tapered. Concomitant with this decrease, there was decreased expression of cell surface activation markers (HLA-DR, CD25 (interleukin 2 receptor) and CD26 (Ta-1)) in peripheral T lymphocytes. There was no significant change in either T lymphocyte subset numbers or mitogen and antigen-specific lymphoproliferation. A regulatory dysfunction of the immune system, allowing inappropriate activation of T lymphocytes, may be involved in the pathogenesis of HIV disease, and further studies involving selective immunosuppression in HIV disease are warranted.

CD4-CD8 Ratio↗
PubMed1993

Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects.

OBJECTIVE: The etiopathogenesis of Behçet's disease (BD) has not yet been clarified but might involve immune dysfunction. As cytokines are involved in the regulation of immune responses and inflammatory reactions, we investigated whether they may play a role in the pathogenesis of BD. METHODS: We investigated spontaneous and lipopolysaccharide (LPS) stimulated production of tumor necrosis factor alpha (TNF alpha), interleukin (IL) 1, IL-6, IL-8 and granulocyte monocyte macrophage colony stimulating factor (GM-CSF) by peripheral blood monocytes from 21 patients with BD, 10 healthy controls and 10 patients with familial Mediterranean fever (FMF), another chronic inflammatory disease. We also studied superoxide generation and surface antigen expression by polymorphonuclear neutrophils (PMN). RESULTS: The spontaneous secretion of TNF alpha, IL-6 and IL-8 by monocytes was significantly increased in patients with active BD. The secretion of TNF alpha, IL-1, IL-6 and IL-8 was found to be in normal range in asymptomatic patients with FMF. The LPS stimulated production of TNF alpha, IL-6, IL-1 and IL-8 was significantly increased in patients with BD, without any correlation with BD activity. In vitro, PMN spontaneously generated significant amounts of superoxide in patients with active BD. CONCLUSION: Taken together, our results suggest that monocyte and PMN dysfunctions may play a role in the pathogenesis of BD.

Adult↗